Heterocyclic diamines and salts thereof



HETEROCYCLIC DIAMINES AND SALTS THEREO Joseph Lester Szaho, Drexel Hill, and William F. Bruce, .Havertown, Pa., assignors, by mesne assignments, to

American Home Products Corporation, New York, N. Y., a corporation of Delaware No Drawing. Original application August 26, 1952, Se-

rial No. 306,514, now Patent No. 2,739,981, dated March 27, 1956. Divided and this application January 18, 1956, Serial No. 559,771 I 4 Claims. '(Cl. zen-332.2

:This invention relates to derivatives of ethylene diamine and itshomologues and, more particularly, to new monoand poly-substituted-amino-alkylene diaminesalts.

' Certain substituted alkylene diamines have been found with bronchodilator and antihistaminic action and also found useful as intermediates in the preparation of desired organic compounds. In addition, it has been discovered that many of these compounds are useful for se'p-. arating penicillin from aqueous solutions by forming a salt therewith. Many of the penicillin salts are substantially insoluble or, at most, sparingly soluble in an aqueous medium. One is thus able to isolate and, if desired, to purify penicillin since it has been found that the latter can be almost quantitatively removed from its solution by the addition of two molecules of penicillin to these particular diamines.

As an additional discovery, these substantially insoluble or sparingly soluble salts of penicillin have been found to be valuable from a pharmacological aspect since they are relatively non-toxic and, when in contact with body fluids, slowly release penicillin for utilization in combatting bacterial infections. A prolonged antibiotic effeet can thus be achieved without difficulty. By the use of these new penicillin salts, one greatly reduces the nutn; ber of injections required to sustain the desired blood level concentration of penicillin. I

The useful diamines are those falling within the following general formulae: y

RNH(CH ),,NH RNH(CH ),,NHR and I RR N(CH ),,NH

where R, R and R may represent either aliphatic,- aromatic, alicyclic or heterocyclic radicals with and without substituents on the rings. In the alkylene portion of the molecule, n is intended to represent a numeral greater than 1, preferably from 2 to 12.

The substituents, which may be on the aryl, alicyclic and heterocyclic rings as well as on the alkyl chain, may comprise one or more alkyl, alkoxy, halogen, nitro, amino, 0x0 or hydroxy ring substituents. As a matter of I fact, with the exception of strong acid or oxidizing groups, no substituent has been found which interferes with the reaction of the N,N'-di-substituted secondary diamines' with penicillin salts to form reaction products therewith In accordance with one method of preparing the disubstituted diamines of the invention, one starts with an" aldehyde or ketone which may, if desired, be'solubilized in a suitable solvent such as alcohol or benzene. aldehyde or ketone is added thealkylene diamine, generally in aqueous solution. is a diimine having the formula:

or by a metal-alcohol or" metal-acid combination.

To the The reaction product, which Where, for example, the radical R, R or R itself contains a double bond, the hydrogenation or reduction may beeither partial, changing only the diimine to a diamine, or complete, with a reduction of the unsaturated radical to a saturated radical. I

.Di-substituted bases may also be formed in some cases Pate'hted Mar. 3, 1959 by a simple substitution reaction, adding the desired sub- T V or'RR N(CH ),,NH may involvethe reduction stituents to the unsubstituted alkylene diamine,

Reactions to form compounds of the type of an amide ;suchas R--CONl-l.-(Cl-l ),,-Nl -I using metalhy drides for -ei tample',-or an amination of a halogen .com-w,

pound such a .-RR N(CH ),,Cl utilizing .ammonia al ethanoL- 1- The poly-substituted bases-can alternatively bemade iby the reaction of an alkylene dihalide, such as the -d1- bromide, dichloride or -diiotlide, with the appropriate amine.

Substituted alkylene diamine salts mayalso be prepared by interacting approximately equivalent quantities of a salt of the alKylenediamine, such as the dihydrochloride,-

dihydrobromide, dinitrate, ditormate, diacetate or other suitable salt of ethylene diamineand an acid, with form-;

aldehyde either in the form of its aqueous solution or as the solid polymeric form, paraformaldehyde, and witha; compound containing an active hydrogen such 'as the: alpha-hydrogen of thiophenes, picolines, quinaldines,

phenols, aliphatic ultra-compounds, organic acids and esters, and open-chain and cyclic aldehydes and ketones' in a suitable solvent such as water, alcohol or other organic-solvents or mixtures thereof, resulting in an N,N'-

disubstituted alkylene diamine salt which may be transposed into the free base by alkali treatment.

ing the penicillin.

The salts may be formed from the free base by dissolving the latter in a solvent, such as ether, to which is added the proper acid, depending on the particular salt desired.

The salts formed may be either mono-salts or di-saltsdepending on the amounts of base and acid used. Thus-,;;

if one mol. equivalent each of acid and base were used,

the mono-salt would be formed. On the other hand, if -two mol. equivalents, or an excess of acid, are used with one mol. of the diamine, the di-salt would be formed'.-' For making penicillin salts from the diamines, one would generally desire the double salt instead of the mono-salt combines with the mono-salt.

Inorganic or organic acids may be used in forming the salts from the free base, amino-substituted alkylene diamines.

chloric, sulfuric, phosphoric, nitric or hydrobromic acids,-

theseforming in general sparingly water-soluble salts.

The most common inorganic acids arehydro On the other hand,:organic aliphatic carboxylic acids are? particularly preferred because in general they have been found to form water-soluble salts and these salts are of definite advantage in forming p'enicillinlsalts of the subwherein R, R and n are the'same as indicated before, is, isolated and is then hydrogenated by catalytic reductionj v p V I u .alkylene-diamines may be mentioned the acids of 1 to 6 stituted alkylene diamines.

Organic acids which have proved useful are the lower boxylic, and tri-carboxylic classes.

tuted compounds and unsaturated aliphatic acids. As

specific examples of organic acids showing'particular usefulness-in formingwater-soluble salts of the substituted:

carbon atoms as formic, acetic, propionic, butyric, iso v valeric, glycolic, lactic, gluconic, amino acetic, and crotonic acids as examples of the mono-carboxylic type. Examples 'of the di-carboxylic class found to be particularly useful are-the acids of 3 to 6 carbon atoms as malonic, succinic, glutaric, adipic, mali'c, tartaric, glutamic, maleic and fumaric acids. In the class of the tricarboxylic acids, citric, iso-citric, and aconitic acids have been found particularly useful. While others will form suitable salts, these organic compounds mentioned will form highly desirable soluble salts whose solubility in water is at least about by weight per unit of liquid volume at about 30' C.

By the term water-soluble salt, the applicants follow thegenera'lly understood meaning. In order to avoid any'question as to meaning, the applicants prefer to con-- si'd era water-soluble salt to be one which will dissolve in water to-the extent of at least about 5% by weight per unit of liquid volume at 30 C. A sparingly water-soluble-salt would be one whosezso'lubility in water would range from just below this figure to about 1% by weight, while a substantially insoluble salt would be one having a solubility less than about 1% by weight per unit of liquidvolume.

In preparing sparingly water-soluble or substantially water-insoluble penicillin salts of 'the amino-substituted alkylene diamine salts, it is highly advantageous to obtain the penicillin salts as a precipitated solid from a substantially aqueous medium. The desired salt may then be easily separated, as-by filtration, and purified by washing. Thus, the selected alkylene diamine salt is solubilized a d reacted with a water-soluble salt of penicillin. The desired penicillin salt. being either substantially water-insolu-. ble or only s aringly water-soluble, precipitates from the aqueous medium and is separated therefrom.

In the above procedure involving precipitation from an aqueous medium, it has been found advantageous to use relatively soluble diamine salts in preparing the penicillin salts thereof since less liquid volume is handled and therefore losses are likely to be less than if relatively insoluble salts were used. While salts made with the inorganic acids can be used in preparing the penicillin compounds, it has been found that their solubility is quite low and well below 5% on a weight basis. Consequently, water-soluble salts and particularly the diacetates,

having a solubility in the neighborhood of about 10% or higher have been found especially effective where it is desiredto handle relatively low liquid volumes and there.

fore high concentrations.

Anyof the known soluble penicillin salts may be combined with the poly-substituted diamines. Thus, one may use the alkali or alkaline earth metal salts of penicillin G, dihydro F, X, or penicillin K for combination with the selected diamine. However, the more preferred penicillin :salts are the sodium or potassium salts of penicillin G. One or two molecules of any penicillin above indicated will unite with one molecule of the diamine, depending on the use of the mono-or the di-salt.

The following examples are given for specific illustrations but it should be understood that these are selected for'illustration of the invention and notto be considered limitative.

EXAMPLE 1,

Preparation N0. 1 01N,N'-dibenzylethylenediamine and salts thereof N,N'-dibenzylethylenediamine was'first prepared by condensing benzaldehyde with ethylene diamine. The dibenzylethylenediamine (23.6 g.) was dissolved in 100 -cc,,methanol containing 0.5 g. Adams platinum catalyst and hydrogenated at 50 lbs. pressure. Slightly more than thetheoretical amount .of hydrogen was absorbed in 45 minutes. The catalyst was filtered off, washed with methanol, ithe .filtrate; concentrated and the. residue irae- 4 tionated. Nearly all of the, material distilled 160 and, 0.75 mm., n 1.5621.

With Raney nickel catalyst at room temperature little hydrogen absorption occurred, however, under elevated pressure hydrogenation went to completion but was much slower than with platinum. The diacetate was prepared by dissolving 440 g. of the base in about 3 liters of 95% alcohol and slowly adding 220 g. of glacial acetic acid. After standing some time the crystalline solid was filtered olf and recrystallized from hot alcohol. Long, white needles, M. P. 1l0-112.

Calcd. for C H N -2CH COOH: C, 66.7; H, 7.78; N, 7.78. Found: C, 66.98; H, 7.63; N, 8.38. Solubility 252.9 g. per liter of solution at 30.4 in water. The dihydrobromide was obtained by adding hydrooromic acid to an aqueous solution of theacetate. Large colorless plates, recrystallized from water, M. P. 300 (bar.). Calcd. for C I-I N -ZHBr: N, 6.97; Br, 39.8. Found: N, 6.9; Br, 39.5. Solubility 30.0 gper liter of solution in water=at 30.4.

The dihydrochloride was obtained from the acetate by addition of hydrochloric acid and recrystallized from Water. Large white plates, M. P. 294 (bar.). Calcd. for C H N -2HCI: N, 8.97; Cl, 22.4. Found: N, 8.8; Cl, 22.4. Solubility 23.9 g. per liter of solution in water at 30.4".

The dinitrate was obtained by adding nitric acid to a solution of the acetate. Large white plates, M. P. 274 (bar.). Calcd. for C H N -HNO N, 15.3. Found: N, 14.9. Solubility 9.04 g. per liter of solution at 30.4".

The phosphate was obtained by adding phosphoric acid to a solution of the acetate and recrystallized from dilute alcohol. White prisms, M. P. 232 (bar.). Calcd. for C H N -2H PO N, 6.42; P, 14.2. Found: N, 5.45; P, 13.9. Solubility 38.6 g. per liter of solution at 30.4.

The sulfate was obtained by addition of sulfuric acid to a solution of the acetate and recrystallization from alcohol. White plates, M. P. 247-250". Calcd. for C1 H N2'H2SO4i C, N, H, S, Found: C, 56.37; H, 6.43; N, 7.99; S, 9.85. Solubility 15.8- g. per liter of solution at 30.4".

The thiocyanate was prepared by addition of a solution of sodium thiocyanate to the acetate and recrystallized from alcohol. White needle-like plates, M. P. 212 (bar.). Calcd. for C H N -2HCNS: N, 15.63. Found: N, 15.4.

The salicylate was'o'otained, by addition of a solution of sodium salicylate to a solution of the acetate and recrystallization from water. White crystals, M. P. (bar.). Calcd. for C H N -2C H O N, 5.42. Found: N, 5.24,

The picrate was obtained from the acetate by addition of a solution of lithium picrate and recrystallization from alcohol, M. P. 211 (bar.).

The oxalate, C H N -H C O was obtained as color less needles from alcohol, M. P. 275-6".

The, salts of the lower aliphatic carboxylic acids mentioned hereinabove did not precipitate out on addition of their aqueous sodium salt solutions to the solutions of the acetate indicating that these salts were substantially water-soluble. To obtain these salts from an aqueous medium, the solutions are evaporated to dryness. A better procedure to obtain a-purified water-soluble product is to ,solubilize the diamine free base in an organic solvent such .as. alcohol, acetone, diethyl ether, etc., and add the free :acid also in solution in an organic solvent. Thede sired sa'lt' will either precipitate from: solution, or thesoh vent solution maybeevaporated to dryness.

The lactate was prepared by mixing alcoholic solutions of'lactic acid and the base, N,N-dibenzyl ethylenediamine. Fine white crystals were obtained having a melting point of 74 C.

The .formate was prepared by adding 4.6 g. of 98100% formic acid dropwise to 12 g. of,N,N'-dibenzyl ethylenediamine .clissolved, in ether. An immediate precipitate asrease formed. The solid was broken up in the ether suspension and filtered off, washed with ether and dried. M. P. 125-126". The salt may be recrystallized from methylethyl ketone.

The glutarate was prepared as with the formate salt but .the addition was reversed, using 0.5 g. of glutaric acid to which was added 0.91 g. of the free base. M. P. 115-118.

The maleate was prepared by first taking 4.9 g. of maleic anhydride and dissolving it in ether to which was added a few cc. of water. After suificient time to permit the formation of the acid, an ethereal solution of 12 g. of free base was added slowly with vigorous agitation. An immediate precipitate of N,N-dibenzyl ethylenediamine maleate formed which was filtered off, washed well with ether and air dried. M. P. 125-128" C.

The succinate was obtained in the following manner. 5.07 grams of succinic acid was dissolved in about 25 cc. of hot alcohol and to it was added a solution of 9.83 grams of the base, N,N-dibenzyl ethylenediamine in about 25 cc. alcohol. Crystals gradually formed. After a few days, these were filtered off, washed with alcohol and dried in the steam oven. White crystals, M. P. 172-174 C. Analysis: calculated on the basis of 1 mol. of base combined with 1 mol. of acid, N calculated 7.82, found 7.00.

The maleate was prepared as above using 5 grams of malic acid and 9 grams of base in about the same quantities of solvent. White crystals formed and were isolated. Analysis: based on 1 mol. of acid and base, N calculated 7.50, found 6.03. Carrying out the same reaction using 2 mols. of acid per mol. of base, a salt product was also obtained. Analysis: N, calcd. 5.5, found, 5.32.

The propionate was prepared in the same manner as above using 5 cc. of base and 3.5 cc. of propionic acid with ether as the solvent. The propionate was obtained in the form of a sirup.

The butyrate was obtained by proceeding as above using 5 cc. of base and 4.1 cc. of isobutyric acid, with ether as the solvent. The butyrate was also obtained in the form of a sirup.

The valerate was obtained by proceeding as above using 5 cc. of base and 4.75 cc. isovaleric acid, with ether as the solvent. A white solid was formed. Softens about 80", M. P. 82-3". Analysis: N, calculated 8,19, found 8.35.

The glycolate was obtained by the above procedure using 10 cc. of base and 4.8 grams of glycolic acid, the solvent being special denatured alcohol No. 30. A white solid was obtained.

The aconitate was prepared in similar manner using 5 cc. of base and 5.45 grams of aconitic acid, the solvent being special denatured alcohol No. 30. The aconitate salt was obtained as a sirup and having an acid reaction. A neutral salt was obtained by changing the amount of aconitic acid used to 7.25 grams.

The adipate was obtained in the form of a salt combining 1 mol. of base with 2 mols. of acid by carrying out the reaction as disclosed above using 10 cc. of base and 6.08 grams of adipic acid, the solvent being special denatured alcohol No. 30. The adipate was a white solid, M. P. 103-105 Analysis: N calculated 5.27, N found 5.27.

The fumarate was obtained by the same procedure using 10 cc. of base and 4.85 grams'of fumaric acid, the solvent being special denatured alcohol No. 30. A white crystal solid salt formed, M. P. 220-223.

The malonate was obtained in the same manner using 10 cc. 'of base'and 5 grams of malonic acid, with ether as the solvent. The salt obtained combined 1 mol. of base with 2 mols. of acid. White solid, M. P. 124-125 Analysis: N calculated 5.86, found 5.79.

In obtaining the following group of salts, these were prepared by adding the free base slowly with stirring to a warm solution of the acid dissolved in the indicated solvent.

The aconitate was obtained using 1.3 grams of aconitic acid and 1.2 grams of base with acetone as the solvent. M. P. 140-142". dec.

The tartarate was obtained using 1.5 grams of d-tartaric acid and 2.4 grams of base, using ethyl alcohol as the solvent. M. P. 215-216".

The crotonate was obtained by reacting 1.8 grams of crotonic acid with 2.4 grams of base, using ethyl alcohol as the solvent. M. P. -1 11.

The citrate was obtained using 7.6 grams citric acid and 14.4 grams base, ethyl alcohol being the solvent. M. P. 201 C. dec.

The gluconate was prepared by reacting 7.12 grams of glucono-A-lactone, the solvent being a mixture of alcohol and water. The salt was obtained in the form of a sirup.

The glycolate was obtained by reacting 2.48 grams of glycolic acid and 4.8 grams of base, with acetone as the solvent, M. P. -121 C.

The glutamate was prepared by reacting 2.5 grams of mono-sodium glutamate with 2.15 grams of N,N'-dibenzyl ethylenediamine diacetate. The sodium salt was dissolved in water, converted to the disodium salt with 4% NaOI-I, pH (final) 8.5. This solution was treated with activated carbon. To the colorless filtrate was added a water solution of the diacetate. The glutamate salt had a melting point of 288-289 C.

In the above cases where solids did not come down immediately, some of the solvent was evaporated off, resulting in a precipitation of salt from the concentrated solution. In those cases where sirups resulted, crystals could sometimes be obtained by evaporation of part of the solvent and stirring or rubbing until crystallization took place. Often, simply standing overnight proved effective.

EXAMPLE 2 Preparation of N,N-dipiperonalethylenediamine and salts thereof Piperonal, g. (1 mol.), was dissolved in 400 cc. ethanol and treated with 35 g. (0.5 mol.) of aqueous ethylenediamine (78%) and allowed to stand a short time (heat is evolved). The resulting white crystalline solid N,N'-dipiperonalethylenediamine was filtered off, washed with alcohol and dried. Yield is theoretical, M. P. 179-180".

A mixture of 388 g. (2.4 mols.) of the above compound in 1500 cc. methanol and 1 g. of Adams platinum catalyst was hydrogenated at 810 lbs/sq. in. until the required amount of hydrogen was taken up. The solution was then concentrated to remove most of the methanol, taken up in water containing acetic acid, and hydrochloric acid then added to obtain the slightly soluble hydrochloride which was recrystallized from hot water, M. P. 277-280". Calcd. for C l-l O N Cl C, 54.0; H, 5.5; N, 7.0; CI, 17.4. Found: C, 54.39; H, 5.41; N, 7.04; Cl, 17.55. p

The hydrochloride was converted to the free base by treatment with strong alkali and extraction with ether. The free base is a white crystalline solid (needles), M. P. 145-8 C.

The diacetate salt, prepared from the free base in ether by addition of glacial acetic acid, is a white crystalline solid, M. P. 133-4 C. Calcd. N, 6.25. Found: 6.25, 6.44. Calcd. M. W. 448. Found: 448.

The flavianate was obtained in yellow crystals, M. P. 230 C. dec. (bar.). The picrate was obtained from acetone in yellow needles, M. P. 216 C. dec.

EXAMPLE 3 Preparation of N.Ndifurfurylethylenediamine and salts thereof grams of ethylenediamine (78%) was vigorously stirred with 500 cc.,benzene in a nitrogen atmosphere 7 while being cooled in ice. Then 454 g. furfural; was slowly added and stirred an hour after addition was'completef The benzene layer; was" removed and dried over solid sodium hydroxide.

Without isolating the above producta portion of the benzene representing 200 g. of product was reduced in 3 liters of absolute alcohol with 350 g. of sodium. The alcohol waspartially removed, Water added and extracted with ether. The ether layer was then dried, the ether removed and the residue fractionated. The N,N'-difurfurylethylenediamine distilled at 131-14l/0.15 mm n 1.5183.

The diacetate, prepared by solution of; the base inether and adding acetic acid followed by recrystallization of the filtered solid from ethyl acetate; formed,

white, needles which melted unsharply about 100-104.

Found: 0, 56.84; 7.02; N, 8.32.

The picrate was obtained as large golden-yellow prismsof M. P. 165167.5 or as large, clear dark-yellow plates-- EXAMPLE 4 Preparation of N,N-bis-(2-thenyl)-ethylenediamine and a salt thereof In a 500 ml. three-necked flask, fitted with stirrer, condenser and thermometer, were mixed 42 g. (0.5 mol.) of thiophene, 33 g. (0.25 mol.) ethylenediamine dihydrochloride and 43 ml. of 36% aqueous formaldehyde (0.5v mol.). The mixture was stirred and heated to gradually raise the temperature. At 60 a vigorous reaction began. Heating was stopped and an ice-bath applied to the flask. The internal temperature rose to 73 and the reaction mixture solidified. 200 ml. of 50% aqueous alcohol were added and stirred and the mixture was heated an additional 1 /2 hours. After cooling, the reaction product was filtered and washed with water. The white product was amorphous and did not dry well, nor could it be crystallized.

It was dissolved in 250 ml. hot water, cooled, and made alkaline with 40% sodium hydroxide.

taken up in benzene, dried over sodium hydroxide and obtained as; a colorless, viscous oil on removing benzene in.;vacuo., The. oil was converted to diacetate by-d-is-.

solving; in 200 ml. ethyl acetate and adding 12 ml. glacial acetic acid. The precipitated. salt was filtered, washed EXAMPLE Preparation .of; N;N-bis-(beta-phenylethyl)'-ethylenedif amine and 'asalt thereof 48.2 g. of beta-phenylethylamine and 18.8 g. ethylene bromide were warmed on. the steam-bath. The reaction was vigorous and after standing some time at roorrrtem-i perature the mass crystallized. The reaction product was made alkaline, extracted with ether and the ether layer extracted with dilute aceticacid. The acid extract was,

made.v alkaline,- extracted% with ether; the ether layer The free base which separated was not very soluble in ether, and was;

3-methyl -isoamino-thiazole, or Z-amino-S-methyl-furan to form the symmetrically di-substituted alkylene diamine and desired salts thereof; The reaction mixture, after making-strongly basic with alkali such as sodium hydroxide, may be extractedwit'n etherand the ether extract distilled to obtain the desired product as a crystalline orsolid residue.

EXAMPLE; 6: Preparation of N-2(alpha-pyridylethyl)ethylenediamine- 26 grams (0.25 mol) of 2-vinyl-pyridine and 9 grams (0.15 mol) of anhydrous ethylenediamine was heated, with stirring, on a steam-bath for 5 hours. The viscous mass was diluted with ether and transferred to a flask for distillation. The ether was removed and the residue distilled under vacuum. B. PL: l04-7 C./0.3 mm.

Analytical.Calculated for N-2(alpha-pyridylethyl)- ethylenediamine: N==25.40, H=9.08, C,=65.52. Found: N=25.42, H=9.09, C=66.03.

Following the procedures disclosed hereinabovc, the. following compounds may be made and fall within, the.

Monosubstltuted diamines Starting materials N-undccylethylenediamine diamine .diformate N-heptylethylenediamine mine dilormate. 3,5,5 trimethylhexaldehyde' and" undecylaldehydeand. ethyleneheptaldehyde and ethylenedia N-(3,5,5-trimethylhexyl)-ethylenediamine. N-2-thenyletbylenediamine N-p-chloro or bromophenyl-ethylene daimine. N.-.vaull1yl ethylenadiamind.

N-'2;.4 or other diehloro or bromo-.

phenylethylene diamine. N-2- or 4-pyridylethylethylenediamine. N-2- or 4-quiuolylethyl ethylenediamine. N 4 methoxyeyclohexyl-ethylenediamlne.

Disubstz'tuteddiaminea N ,N di n heptylethylene di am e. N,N diundecyl ethylenediamine.

N,N dicyclopentylethylene diamine.

N,N di 4 methoxy cyclohexylethylene diamine.

N,N divanillylethylenediamine.

N eyclohexyi N ethylethylenediamine.

N henzyl -.N' vanillylethylene lamina.

N methyl N phenylethylene dia mine.-

N,N' di undecylenylethylenedi;

amine.

N,'N"- di omega -.brompropylethylenediamine.

N,'N di omega hydroxypropyltrimethylenediamine.

N;N di betavinyloxyethylethylenediamine.

N,N-di-beta-earhoxamidomethylethylenediamine;

ethylenediamine diformate. thiophene, formaldehyde, ethylenediamine-di HCl salt. N-phenylethylene diamine and Ch or B vanillin,

Ch or Bra.

2- or 4-pioollne, formaldehyde,-

ethyienediamine- (ii-H01 salt. 2- or 4-quinaldine, formaldehyde,

ethylene-diamine di-H'Cl salt. 4 methoxycyclohexanone andethylenediamlne dlformate.

heptaldehtyde, ethylenedlamine diforma undecylaldehyde, ethylenedlamlne.

(ii formate. eyclopentanone, ethylenediamlne;

diformate.

enediamine dil'orm e.

vanillin, ethylenediamine dil'or- N cyciohexylethylenediamine,

acetaldehyde, Hg,(n:).

N benzylethylene diamine,

vanillin, formic acid.

methyl aniline, chloracotnl, fol

lowed by anun0niu n tormnter formic acid;

utijdecylenoylchloride. ethylene lamina; followed by, reduction with lithium aluminum hydride.

N ,N diallylethylcnediamine and.

hydrobromic acid trimethylenechloroliydrin and trlmethyloncdiamine. vinyl beta chlorethylether and: ethylenedian iner hloraceta ide. and. ethylened amine.-

ethylenediamine. 3,011:- m .e.

N-phenylethylene diamine and? 2,ave,2se

9 The following examples illustrate the preparation of. penicillin salts from the corresponding substituted alkylene diamines.

EXAMPLE 7 Preparation of N,N'-dipiperonylethylenediamine di-penicillin-G To a solution of 1.07 g. sodium penicillin in about 2 ml. cold water, a solution of 0.7 g. N,N'-dipiperonylethylenediamine acetate in about 2 ml. cold water was slowly added with stirring. The white insoluble solid was filtered elf, washed with water and dried over phosphorus pentoxide.

EXAMPLE 8 N,N'-difurfurylethylenediamine di-penicilIin-G Sodium penicillin (1.07 g.) is dissolved in about 2 ml. water cooled in an ice-bath. To the clear solution, 0.5 g. of N,N'-difurfurylethylenediamine acetate dissolved in about-2 ml. of cold water is slowly added with stirring. A white, insoluble, crystalline powder is formed which is filtered olf, washed with cold water and dried in a desiccator over phosphorus pentoxide.

it is obvious that the insoluble organic base penicillin salts formed contain two mols. of penicillin for each moi. of organic base when a di-salt of the substituted diamine is used and when an excess of penicillin salt is present, as is indicated by the analysis of the N,Ndibenzylethylenediamine salt, and by the assays of the N,N-dibenzyl-, N,N'-difurfuryl and. N,N'-dipiperonyl-ethy1enediamine penicillin salts. The best procedure for insuring the formation of a di-salt is to add the base-salt water solution into the acid or penicillin solution, and if relatively large crystals are desired, the rate of addition should be slow with a relatively low concentration during reaction. Another way to insure the formation of a di-salt is to add the two aqueous solutions simultaneously in such a way as to get equivalent amounts reacting at any one time.

It is also possible to obtain the mono-salt, that is the combination of one rnol. organic base to one rnol. of penicillin. If one were to reverse the addition described above, namely by adding the solution of penicillin salt to the water solution of the base salt, one could obtain the mono-penicillin salt.

Penicillin salts can also be prepared by adding nonaqueous solutions of free penicillin to non-aqueous solutions of the organic bases by using suitable solvents such as ether, acetone, ethylacetate, amylacetate, etc. This procedure can be carried out provided one avoids an excess of base which inactivates or decomposes the peniciilin.

Besides the penicillin salts hereinabove described and those made from the alkylenediamines mentioned, the following monoand di-penicillin salts are also deemed useful for the reasons indicated.

N-octylethylenediamine di-penicillin N,N'-di-methallylethylenediamine di-penicillin N,N'-di-propargylethylenediamine di-penicillin N,N-dicrotylethylenediamine di-penicillin N,N-di-phenylethylenediamine di-penicillin N,N'-di-1(or 2) naphthyl ethylenediamine di-penicillin N,N'-di-2-pyridylethylenediamine di-penicillin N-bcnzhydrylethylenediamine di-penicillin N,N'-di-benzhydrylethylenediamine di-penicillin N-veraterylethylenediamine di-penicillin N,N'-di-veraterylethylenediamine di-penicillin N-benzyl-N'-p-methoxybenzylethylenediamine di-penicillin N,N'-dibenzyl-l-methylethylenediamine di-penicillin N,N-dicyclohexylethylenediamine mono-penicillin N,N-diamyl ethylenediamine mono-penicillin N-ethyl-N-phenyiethylenediamine mono-penicillin Preparation of trative examples, are listed with their melting points:

Form 01 dig enlciilin-G M. P., 0. Organic base salt a t N Ndilgenzylethylenediamine White crystalline pwd-.. ca. 110-135 ace a e.

N, N'-dipiperonylethylene- White pwd. or colorless 112-119 diamine diacctate. crystals.

N, N'-bis-(p-chlorobenzyl)- White crystals 110-117 ethylenediamine diacetate.

N, N-bis-(2, 4-dichlorobenzyl)- Yellowish prisms. -100 ethylenediamine dlacetate.

N, N-bis-(p-nitrobenzyl)- White crystals 95-100 ethylenediamine diacetate.

N, N-bis-(p-hydroxybenzyb- ..do 140-145 ethylenediamine dihydrochloride.

N, N'-bls-(p-methoxybenzyl)- ....do -103 ethylenediamine diacetate.

N, N-bis-(p-aminobenzyl)- White, granular crystals. 144-8 ethylenediamine dihydro- 144-8 chloride.

N-benzyl-N-(alpha-ethyl- White crystals -8 benzyD-ethylcnediamine dih ydrochloride.

N, N -bis-(beta-phenylethyl)- do 95-102 ethylenediamine diacetate.

N, N -bis-(gamrna-phenyldo 78-83 propyl)-ethylenediamine dihydrochloride.

1,3-bis-(benzyiamino)propane do 100-102 diacetate.

1,5-bis-(benzylamino)-pentane White glass... -140 diacetate.

N, N -difurfurylethylene- White crystalline pwd--- 83-86 diamine diacetate.

N, N-di-2-thenylethylene- White crystals -7 diamine diacetate.

N, N -dlcyclohexylethylenedo -6 diamine diacetate.

N, N -bis-(4-methyl-2-pentyl)- Colorless solid ethylenediamine diacetate.

N, N -bis-(2-heptyl)-ethylene- Crystalline solid..... 75-85 diamine diacetate.

N, N'-bis-(3, 5, fi-trimethyl- White crystals 90-95 hexyi)-ethylenedlamine diacetate.

N, N -bis-(p-methylbcnzyl)- '....do 90-97 ethylenediamine dlacetate.

1, 10-bls-(benzylamino)-decane White solid 106 diacetate.

N, N '-bis-(ethyl)-ethylene- White, crystals 172-3 diamine-dlhydrochlorlde.

N, N -bis-(n-propyl)- White, granular.-... 120

ethylenediamine dlacetate.

N, N -l rls-(lsopropyl)-ethylene- Fine white crystals 145-150 diamine dlacetate.

N, N-bls-(n-butyD-ethylenedo 155-163 diamine diacetate.

N, N -bis-(isobutyl)-ethylene- White solid 127-129 diamine diacetate.

N, N '-hls-(sec. butyl)- White, granular 135-145 ethylenediamine diacetate.

N, N -bls-(l-cyclopropylethyl)- White crystals 73 ethylenediamine dihydrochloride.

N, N-bis-(hexahydrobenzyl)- do 151 ethylenediamine dihydrochloride.

N, N -bis-(4-methylcyclohexyldo 156 1)-ethylenediamine dihydrochloride.

N, N -dimethy lethylenediamine White solid 147-140 dihydrochloride.

N, N-dibenzhydrylethylene- 118-119 diamine-dihydrochloride.

N-methyl-ethylenediamine- 252-3 dihydrochlorlde.

N-dodecyl-ethylcnediamine- 232-3 dihydrochloride.

N, N -di-beta-ethoxyethyl- 85-90 ethylenediamine diacetate.

N, N -di-allylethylenediamine White crystals above 85 dihydrochloride. (foam) N, N -diisopropyl-decam- White solid ethylenedlamine-diiodide.

N, N -di-n-octyldecamethylene- -.do 176 dismine-diacetate.

N, N -di-beta-cycl0hexylethyldo 118-120 ethylenediamine-dihydroc oride.

N -(2-methoxy-6-chloro-9- Yellow solid above 155 acrldyD-ethylenediamine (foam) diacetate.

N -m0no-beta-cyclohexyletbyl- White solid 231-3 ethylenediamine-dihydrochloride.

1, 2-ethylenediarnine-bisdo 108 (N -2-heptyl acetamide) diacetate.

With regard to crystal size, the rapid addition of a and diflicult to wash. Where relatively large crystals are amines could be used in any stage of the recoveryprocess for the isolation of penicillin. Since .a substantial number of compounds, particularly ;those of higher molecular weight, areeitherinsoluble or only sparingly soluble in water, a precipitationfrom the buffered penicillin extract is possible. With regard. to N,N dibenzylethylenediamine, for example, the free base could be used for precipitation of penicillinfrom the amyl-acetate extracting liquors sincethe base is soluble in this medium. The diacetate or any other water-soluble salt could, of course, be used for the aqueousprecipitation. The versatility of thesecompounds is clearly obvious.

When the diamine penicillin salts are used for therapeutic purposes, they may be used for injection either with a spreading agent such-as hyaluronidase, with a suspending agent such as carboxymethyl cellulose ,or pectin, or in a vegetable oil vehicle either with beeswax or-alu minum monostearate gel, the composition being made up in-substantially the same manner'as any other sparingly soluble penicillin salt ,known to the art.

The diamine penicillin salts herein disclosedvaryvin their solubility in water .from sparing solubility to substantial insolubility. Because of this action, there is a variation in their therapeutic effects ranging fromquickly measurable blood levels to delayed blood level measurements. The clinician is therefore given a wide choice of penicillin products with varying times of onset of action. Further variations, may be made by mixingffastacting and slow-acting compounds, -.whether this involves combinations of the diamine penicillin or combinations of procaine penicillin or other known compounds with one or more compounds .of v,the invention.

Many modifications and changes within the skill of the art are contemplated without departing from the scope of the invention as defined inthe-appended claims.

This application is .a division of application Serial No. 306,514, filed August 26, 1952, now .Patent No. 2,739,- 98.1, which in turn is a continuationin-part of application Serial No. 174,115, filed July 15, .1950, now Patent No. 2,627,491.

We claim:

1. As new compounds, the water-soluble, lower aliphatic acid-addition salts of an 'alkylene diamine having the formula wherein R andR represent similar heterocyclic-radicals and, selected from the group ,consisting of .piperonyl, ,furfuryl andthenyl radicals.

,2. The new compound, N,N'-dipiperonylethylenediamine diacetate.

3. The new compound, N,N-difnrfurylethylenediamine diacetate.

4. The new compound, N,N-bis-(.2-thenyl)-ethylenediamine diacetate.

References Cited in the ffile of this patent UNITED STATES PATENTS 2,222,354 Litchty Mar. 19, 1940 2,581,868 Kyrides Jan. 8, 1952 2,627,491 Szabo et'al. Feb. 3, 1953 2,667,494 Emerson 12111.26, 1954 OTHER REFERENCES Zienty: J. A. C. S., 67: 1040-1 (1945).

Lob: Rec. Trav. Chim., 865 (1936).

Houben: Methoden der Organischen Chernie, vol. 4, page 31 2 (Part 2), Geory Thieme Verlay, Stuttgart, Germany, 4th ed.

UNITED STATES PATENT OFFICE Certificate of Correction Patent No. 2,876,236 March 3, 1959 Joseph Lester Szabo et al.

It is hereby certified that error appears in the printed specification of the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 3, line 70, for dibenzylethylenediamine read -dibenzalethylenediamine-; column 4, line 29, Example I, for

O H2 N 'HNOa read C16H20N2 '2HNO8 line 50, for OISH2ON2'2C7H1GO3 read -O16H20N2 2G7H603; Column 6, line EX ample 2, in the headlng, for "-dpiperonalethylenediamine read dipipemnyZetky Z- enedz'amz'ne; for (ban) Wherever it appears in the patent read -(bar)-.

Signed and sealed this 15th day of September 1959.

Attest KARL H. AXLINE, ROBERT C. WATSON, Attestz'ng Oyfieer. C'ommzssz'oner of Patents. 

1. AS NEW COMPOUNDS, THE WATER-SOLUBLE, LOWER ALIPHATIC ACID-ADDITION SALTS OF AN ALKYLENE DIAMINE HAVING THE FORMULA 